tbuckley/cabot-search huggingface dataset:
Comparative risk of acute kidney injury among cancer patients treated with immune checkpoint inhibitors
Authors: Fei Liu, Zixian Wang, Xiaofan Li, Zhen Zhang, Yue Yang, Junquan Chen, Dinghua Chen, Lingling Wu, Xiangyu Liu, Sujun Han, Fangming Wang, Wasilijiang Wahafu, Yibo Gao, Shancheng Ren, Nianzeng Xing, Guangyan Cai, Xiangmei Chen
Journal: Cancer Communications (2022)

Abstract With the development and introduction of immune checkpoint inhibitors (ICIs) in cancer patients, immune‐related side effects have increasingly attracted attention. However, the risks of immune‐related renal toxicity are poorly characterized. In this study, we performed a network meta‐analysis (NMA) of ICI‐related randomized clinical trials (RCTs) to elucidate the comparative risk of acute kidney injury (AKI) in cancer patients receiving different ICIs. We also sought to identify other factors potentially affecting the risk of AKI. PubMed and EMBASE were searched for peer‐reviewed trial reports published between January 2000 and May 2021. Eligible studies were RCTs studying ICIs in cancer patients and reporting AKI data. We performed a frequentist NMA to evaluate the risk ratios for grade 1‐5 and grade 3‐5 AKI between the treatment groups. We also assessed the absolute incidence of AKI in the ICI‐containing arm using traditional direct meta‐analysis. Once significant heterogeneity was detected in a traditional direct meta‐analysis, multivariable meta‐regression analysis was applied to identify factors that significantly affected the absolute incidence of AKI. A total of 85 RCTs were included in this study. In the NMA for the risk of grade 1‐5 and 3‐5 AKI, ipilimumab showed a significantly higher risk than avelumab and durvalumab, whereas 1 mg/kg nivolumab plus 3 mg/kg ipilimumab (N1I3) showed a significantly higher risk than other groups. In terms of treatment ranking, durvalumab ± low‐dose tremelimumab and avelumab were consistently among the top three safest treatments for grade 1‐5 or 3‐5 AKI, whereas N1I3, ipilimumab and tremelimumab were consistently among the top three treatments with the highest risk for grade 1‐5 or 3‐5 AKI. Compared with other cancers, renal cell carcinoma and urothelial carcinoma showed a significantly higher risk of AKI. The incidence of AKI was significantly higher with ICI+chemotherapy than with ICI monotherapy. In this NMA involving large‐scale up‐to‐date ICI trials, we demonstrated the comparative safety of existing ICI drugs for grade 1‐5 and grade 3‐5 AKI. Based on data from the ICI arms of these trials, we also revealed several potential risk factors for immune‐related AKI, including tumor type and treatment paradigm.
Multifunctional metal-organic framework (MOF)-based nanoplatforms for cancer therapy: from single to combination therapy
Authors: Jie Yang, Dihua Dai, Xi Zhang, Lesheng Teng, Lianjun Ma, Ying-Wei Yang
Journal: Theranostics (2022)

Cancer remains a severe threat to human health. To date, although various therapeutic methods, including radiotherapy (RT), chemotherapy, chemodynamic therapy (CDT), phototherapy, starvation therapy, and immunotherapy, have entered a new stage of rapid progress in cancer theranostics, their limited therapeutic effect and significant side effects need to be considered carefully. With the rapid development of nanotechnology, the marriage of nanomaterials and therapeutic methods provides the practical possibility to improve the deficiencies in cancer therapy. Notably, metal-organic frameworks (MOFs) composed of ions/clusters and bridging ligands through coordination bonds have been widely applied in cancer therapy to deal with the drawbacks of different therapeutic methods, such as severe side effects, low stability, and poor efficacy, owing to their controllable morphologies, tailorable diameters, diverse compositions, tunable porosities, high specific surface areas, facile functionalization, and good biocompatibility. This review summarizes the recent advanced developments and achievements of multifunctional MOF-based nanoplatforms for cancer therapy through single therapy methods, including RT, chemotherapy, CDT, phototherapy (photodynamic and photothermal therapy), starvation therapy and immunotherapy, and combination therapy methods. Moreover, the prospects and challenges of MOF-based nanoplatforms used in tumor therapy are also discussed.
Nanomaterial-based CT contrast agents and their applications in image-guided therapy
Authors: Zeyu Jiang, Meihua Zhang, Peifeng Li, Yin Wang, Qinrui Fu
Journal: Theranostics (2022)

Computed tomography (CT), a diagnostic tool with clinical application, comprehensive coverage, and low cost, is used in hospitals worldwide. However, CT imaging fails to distinguish soft tissues from normal organs and tumors because their mass attenuation coefficients are similar. Various CT contrast agents have been developed in recent years to improve the sensitivity and contrast of imaging. Here, we review the progress of nanomaterial-based CT contrast agents and their applications in image-guided therapy. The CT contrast agents are classified according to their components; gold (Au)-based, bismuth (Bi)-based, lanthanide (Ln)-based, and transition metal (TM)-based nanomaterials are discussed. CT image-guided therapy of diseases, including photothermal therapy (PPT), photodynamic therapy (PDT), chemotherapy, radiotherapy (RT), gas therapy, sonodynamic therapy (SDT), immunotherapy, starvation therapy, gene therapy (GT), and microwave thermal therapy (MWTT), are reviewed. Finally, the perspectives on the CT contrast agents and their biomedical applications are discussed.
Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression
Authors: Sehyun Oh, Sihyang Jo, Martina Bajzikova, Han Sun Kim, Thien T. P. Dao, Jakub Rohlena, Jin-Mo Kim, Jiri Neuzil, Sunghyouk Park
Journal: Theranostics (2022)

Rationale: Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth. Methods and results: Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression in vivo. Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation. Conclusion: Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.
Simplified one-pot <sup>18</sup>F-labeling of biomolecules with <i>in situ</i> generated fluorothiophosphate synthons in high molar activity
Authors: Hongzhang Yang, Lei Zhang, Huanhuan Liu, Yunming Zhang, Zhaobiao Mou, Xueyuan Chen, Jingchao Li, Fengming He, Zijing Li
Journal: Theranostics (2022)

Rationale: Conventional 18F-labeling methods that demand substrate pre-modification or lengthy radiosynthesis procedures have impeded the visualization and translation of numerous biomolecules, as biomarkers or ligands, using modern positron emission tomography techniques in vivo. Moreover, 18F-labeled biomolecules in high molar activity (Am) that are indispensable for sensitive imaging could be only achieved under strict labeling conditions. Methods: Herein, 18F-labeled fluorothiophosphate (FTP) synthons in high Am have been generated rapidly in situ in reaction solutions with < 5% water via nucleophilic substitution by wet [18F]F-, which required minimal processing from cyclotron target water. Results: Various 18F-labeled FTP synthons have been prepared in 30 sec at room temperature with high radiochemical yields > 75% (isolated, non-decay-corrected). FTP synthons with unsaturated hydrocarbon or activated ester group can conjugate with typical small molecules, peptides, proteins, and metallic nanoparticles. 337-517 GBq μmol-1 Am has been achieved for 18F-labeled c(RGDyK) peptide using an automatic module with 37-74 GBq initial activity. Conclusion: The combination of high 18F-fluorination efficiency of FTP synthons and following mild conjugation condition provides a universal simplified one-pot 18F-labeling method for broad unmodified biomolecular substrates.
BAG2 drives chemoresistance of breast cancer by exacerbating mutant p53 aggregate
Authors: Xinjian Huang, Dongni Shi, Xuxiazi Zou, Xuxia Wu, Shumei Huang, Lingzhi Kong, Muwen Yang, Yunyun Xiao, Boyu Chen, Xiangfu Chen, Ying Ouyang, Libing Song, Yunting Jian, Chuyong Lin
Journal: Theranostics (2022)

Rationale: Chemoresistance is a major challenge in the clinical management of patients with breast cancer. Mutant p53 proteins tend to form aggregates that promote tumorigenesis in cancers. We here aimed to explore the mechanism for the generation of mutant p53 aggregates in breast cancer and assess its role in inducing chemoresistance. Methods: Expression of BCL2-associated athanogene 2 (BAG2) was evaluated by qRT-PCR, western blotting, and immunohistochemistry in breast cancer patient specimens. The significance of BAG2 expression in prognosis was assessed by Kaplan-Meier survival analysis and the Cox regression model. The roles of BAG2 in facilitating the formation of mutant p53 aggregates were analyzed by co-immunoprecipitation, immunofluorescence, and semi-denaturing detergent-agarose gel electrophoresis assays. The effects of BAG2 on the chemoresistance of breast cancer were demonstrated by cell function assays and mice tumor models. Results: In the present study, we found that BAG2 was significantly upregulated in relapse breast cancer patient tissues and high BAG2 was associated with a worse prognosis. BAG2 localized in mutant p53 aggregates and interacted with misfolded p53 mutants. BAG2 exacerbated the formation of the aggregates and recruited HSP90 to promote the propagation and maintenance of the aggregates. Consequently, BAG2-mediated mutant p53 aggregation inhibited the mitochondrial apoptosis pathway, leading to chemoresistance in breast cancer. Importantly, silencing of BAG2 or pharmacological targeting of HSP90 substantially reduced the aggregates and increased the sensitivity of chemotherapy in breast cancer. Conclusion: These findings reveal a significant role of BAG2 in the chemoresistance of breast cancer via exacerbating mutant p53 aggregates and suggest that BAG2 may serve as a potential therapeutic target for breast cancer patients with drug resistance.
Epigenetic drugs in somatostatin type 2 receptor radionuclide theranostics and radiation transcriptomics in mouse pheochromocytoma models
Authors: Martin Ullrich, Susan Richter, Josephine Liers, Stephan Drukewitz, Markus Friedemann, Jörg Kotzerke, Christian G. Ziegler, Svenja Nölting, Klaus Kopka, Jens Pietzsch
Journal: Theranostics (2022)

Pheochromocytomas and paragangliomas (PCCs/PGLs) are catecholamine-producing tumors.In inoperable and metastatic cases, somatostatin type 2 receptor (SSTR2) expression allows for peptide receptor radionuclide therapy with [ 177 Lu]Lu-DOTA-TATE.Insufficient receptor levels, however, limit treatment efficacy.This study evaluates whether the epigenetic drugs valproic acid (VPA) and 5-Aza-2'-deoxycytidine (DAC) modulate SSTR2 levels and sensitivity to [ 177 Lu]Lu-DOTA-TATE in two mouse PCC models (MPC and MTT).Methods: Drug-effects on Sstr2/SSTR2 were investigated in terms of promoter methylation, mRNA and protein levels, and radiotracer binding.Radiotracer uptake was measured in subcutaneous allografts in mice using PET and SPECT imaging.Tumor growth and gene expression (RNAseq) were characterized after drug treatments.Results: DAC alone and in combination with VPA increased SSTR2 levels along with radiotracer uptake in vitro in MPC (high-SSTR2) and MTT cells (low-SSTR2).MTT but not MPC allografts responded to DAC and VPA combination with significantly elevated radiotracer uptake, although activity concentrations remained far below those in MPC tumors.In both models, combination of DAC, VPA and [ 177 Lu]Lu-DOTA-TATE was associated with additive effects on tumor growth delay and specific transcriptional responses in gene sets involved in cancer and treatment resistance.Effects of epigenetic drugs were unrelated to CpG island methylation of the Sstr2 promoter. Conclusion:This study demonstrates that SSTR2 induction in mouse pheochromocytoma models has some therapeutic benefit that occurs via yet unknown mechanisms.Transcriptional changes in tumor allografts associated with epigenetic treatment and [ 177 Lu]Lu-DOTA-TATE provide first insights into genetic responses of PCCs/PGLs, potentially useful for developing additional strategies to prevent tumor recurrence.
EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules
Authors: Yue Liu, Ka Sin Lui, Zuodong Ye, Tsz Yan Fung, Luo Chen, Ping Yiu Sit, Chin Yu Leung, Nai Ki Mak, Ka-Leung Wong, Hong Lok Lung, Yoshimasa Tanaka, Allen Ka Loon Cheung
Journal: Theranostics (2022)

Nasopharyngeal carcinoma (NPC) is a diverse cancer with no well-defined tumor antigen, associated with oncogenic Epstein-Barr Virus (EBV), and with usually late-stage diagnosis and survival <40%.Current radiotherapy and chemotherapy have low effectiveness and cause adverse effects, which calls for the need of new therapy.In this regard, adoptive immunotherapy using γδ T cells has potential, but needs to be coupled with butyrophilin 2A1 and 3A1 protein expression to achieve tumoricidal effect.Methods: Human γδ T cells were expanded (with Zol or PTA) and used for cytotoxicity assay against NPC cells, which were treated with the EBV EBNA1-targeting peptide (L2)P4.Effect of (L2)P4 on BTN2A1/BTN3A1 expression in NPC cells was examined by flow cytometry and Western blot.An NPC-bearing NSG mice model was established to test the effectiveness of P4 and adoptive γδ T cells.Immunofluorescence was performed on NPC tissue sections to examine the presence of γδ T cells and expression of BTN2A1 and BTN3A1.EBV gene expression post-(L2)P4 treatment was assessed by qRT-PCR, and the relationship of LMP1, NLRC5 and BTN2A1/BTN3A1 was examined by transfection, reporter assay, Western blot, and inhibition experiments.Results: Zol-or PTA-expanded the Vδ2 subset of γδ T cells that exerted killing against certain NPC cells.(L2)P4 reactivates latent EBV, which increased BTN2A1 and BTN3A1 expression and conferred higher susceptibility towards Vδ2 T cells cytotoxicity in vitro, as well as enhanced tumor regression in vivo by adoptive transfer of Vδ2 T cells.Mechanistically, (L2)P4 induced EBV LMP1, leading to IFN-γ/p-JNK and NLRC5 activation, and subsequently stimulated the expression of BTN2A1 and BTN3A1.Conclusions: This study demonstrated the effectiveness of using the EBV-targeting probe (L2)P4 and adoptive γδ T cells as a promising combinatorial immunotherapy against NPC.The identification of the LMP1-IFN-γ/p-JNK-NLRC5-BTN2A1/BTN3A1 axis may lead to new insight and therapeutic targets against NPC and other EBV + tumors.
Ablation of NLRP3 inflammasome attenuates muscle atrophy via inhibiting pyroptosis, proteolysis and apoptosis following denervation
Authors: Zongqi You, Xinying Huang, Yaoxian Xiang, Junxi Dai, Lei Xu, Junjian Jiang, Jianguang Xu
Journal: Theranostics (2022)

Rationale: The inflammasome has been widely reported to be involved in various myopathies, but little is known about its role in denervated muscle. Here, we explored the role of NLRP3 inflammasome activation in experimental models of denervation in vitro and in vivo. Methods: Employing muscular NLRP3 specific knock-out (NLRP3 cKO) mice, we evaluated the effects of the NLRP3 inflammasome on muscle atrophy in vivo in muscle-specific NLRP3 conditional knockout (cKO) mice subjected to sciatic nerve transection and in vitro in cells incubated with NLRP3 inflammasome activator (NIA). To evaluate the underlying mechanisms, samples were collected at different time points for RNA-sequencing (RNA-seq), and the interacting molecules were comprehensively analysed. Results: In the experimental model, NLRP3 inflammasome activation after denervation led to pyroptosis and upregulation of MuRF1 and Atrogin-1 expression, facilitating ubiquitin-proteasome system (UPS) activation, which was responsible for muscle proteolysis. Conversely, genetic knockout of NLRP3 in muscle inhibited pyroptosis-associated protein expression and significantly ameliorated muscle atrophy. Furthermore, cotreatment with shRNA-NLRP3 markedly attenuated NIA-induced C2C12 myotube pyroptosis and atrophy. Intriguingly, inhibition of NLRP3 inflammasome activation significantly suppressed apoptosis. Conclusions: These in vivo and in vitro findings demonstrate that during denervation, the NLRP3 inflammasome is activated and stimulates muscle atrophy via pyroptosis, proteolysis and apoptosis, suggesting that it may contribute to the pathogenesis of neuromuscular diseases.
Zwitterionic rhodamine-CPT prodrug nanoparticles with GSH/H<sub>2</sub>O<sub>2</sub> responsiveness for cancer theranostics
Authors: Xueluer Mu, Zejian Huang, Wenbi Feng, Manyu Zhai, Yukun Wang, Dan Zhou, Xianfeng Zhou
Journal: Theranostics (2022)

Rationale: Fluorescently traceable prodrugs, which can monitor their biodistribution in vivo and track the kinetics of drug delivery in living cells, are promising for constructing theranostic medicines. However, due to their charge and hydrophobicity, most of the fluorescently traceable prodrugs exhibit high protein binding and non-specific tissue retention affecting in vivo distribution and toxicity, with high background signals. Methods: Herein, the zwitterionic rhodamine (RhB) and camptothecin (CPT) were bridged with a disulfide bond to construct a tumorous heterogeneity-activatable prodrug (RhB-SS-CPT). The interaction of zwitterionic RhB-SS-CPT with proteins was detected by UV and fluorescence spectroscopy, and further demonstrated by molecular docking studies. Then, intracellular tracking and cytotoxicity of RhB-SS-CPT were determined in tumor and normal cells. Finally, the in vivo biodistribution, pharmacokinetics, and anticancer efficacy of RhB-SS-CPT were evaluated in a mouse animal model. Results: The tumorous heterogeneity-activatable RhB-SS-CPT prodrug can self-assemble into stable nanoparticles in water based on its amphiphilic structure. Particularly, the zwitterionic prodrug nanoparticles reduce the non-specific binding to generate a low background signal for better identification of cancerous lesions, achieve rapid internalization into cancer cells, selectively release bioactive CPT as a cytotoxic agent in response to high levels of GSH and H2O2, and exhibit high fluorescence that contributes to the visual chemotherapy modality. In addition, the RhB-SS-CPT prodrug nanoparticles show longer circulation time and better antitumor activity than free CPT in vivo. Interestingly, the zwitterionic nature allows RhB-SS-CPT to be excreted through the renal route, with fewer side effects. Conclusions: Zwitterionic features and responsive linkers are important considerations for constructing potent prodrugs, which provide some useful insights to design the next-generation of theranostic prodrugs for cancer.
Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer
Authors: Wenjie Guo, Yang Liu, Xiaoying Ji, Shanshan Guo, Fanfan Xie, Yanxing Chen, Kaixiang Zhou, Huanqin Zhang, Fan Peng, Dan Wu, Zhenni Wang, Xu Guo, Qi zhao, Xiwen Gu, Jinliang Xing
Journal: Theranostics (2022)

Rationale: Mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutations and subsequent metabolic defects are closely involved in tumorigenesis and progression in a cancer-type specific manner. To date, the mutational pattern of mtDNA somatic mutations in colorectal cancer (CRC) tissues and its clinical implication are still not completely clear. Methods: In the present study, we generated a large mtDNA somatic mutation dataset from three CRC cohorts (432, 1,015, and 845 patients, respectively) and then most comprehensively characterized the CRC-specific evolutionary pattern and its clinical implication. Results: Our results showed that the mtDNA control region (mtCTR) with a high mutation density exhibited a distinct mutation spectrum characterizing a high enrichment of L-strand C > T mutations, which was contrary to the H-strand C > T mutational bias observed in the mtDNA coding region (mtCDR) (P < 0.001). Further analysis clearly confirmed the relaxed evolutionary selection of mtCTR mutations, which was mainly characterized by the similar distribution of hypervariable region (HVS) and non-HVS mutation density. Moreover, significant negative selection was identified in mutations of mtDNA complex V (ATP6/ATP8) and tRNA loop regions. Although our data showed that oxidative metabolism was commonly increased in CRC cells, mtDNA somatic mutations in CRC tissues were not closely associated with mitochondrial biogenesis, oxidative metabolism, and clinical progression, suggesting a cancer-type specific relationship between mtDNA mutations and mitochondrial metabolic functions in CRC cells. Conclusion: Our study identified the CRC-specific evolutionary mode of mtDNA mutations, which is possibly matched to specific mitochondrial metabolic remodeling and confers new mechanic insight into CRC tumorigenesis.